Description (Applicant's Abstract): Narcolepsy is characterized by overwhelming sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. Genetic studies have identified a link between narcolepsy and HLA haplotype. Because the HLA region specifies the proteins used to present antigen and because most HLA linked diseases are autoimmune, it has been suggested that narcolepsy is an autoimmune disease. However, there is no convincing evidence for this hypothesis. During the current grant period we have found the first evidence for a neurodegenerative process in narcolepsy. Studying narcoleptic dogs, we saw that degeneration occurred over a relatively short time period and was localized to basal forebrain, amygdala and adjacent regions. These regions are known to have key roles in the control of sleep and in the regulation of brainstem motor tone control systems. The highly localized nature of the degeneration and the relatively short duration of the degenerative events may explain the failure to find evidence for active immune processes in fully symptomatic human or canine narcoleptics. We conducted a pilot study of the effects of immunosuppression on narcoleptic dogs during the period of degeneration, using glucocorticoids, azathioprine and methotrexate. We saw a delay of symptom onset and a marked reduction of symptom intensity in all treated animals. The change in symptom severity appears to be permanent. We also found evidence that immune activation exacerbates symptomatology. If verified in a larger group of animals, these would be the first manipulations shown to affect the course of the narcoleptic disease process, and would be important evidence for immune system involvement in the pathogenesis of narcolepsy. In further pilot work, we saw CD3+ T cells at the sites of degeneration in untreated narcoleptics, key evidence for immune involvement. We propose to study the effect of immunosuppression on the development of narcolepsy. We will determine whether we can completely prevent the development of symptoms with combined prednisone and methotrexate treatment. We will see whether there is a critical period for intervention. We will determine whether immune activation exacerbates symptomatology. We will look for evidence of lymphocytes and activated microglia at the sites where we have seen degeneration. This work could lead to a treatment for human narcolepsy and to a better understanding of the cause of this debilitating disease.